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Identifying potential drug targets for cerebral amyloid angiopathy: A Mendelian randomization study based on the
Jiuchang Zhang1,2, Anmu Xie1, Zhongrui Yan2
1Department of Neurology, Affiliated Hospital of Qingdao University, Qingdao, China.
Insights
Cerebral amyloid angiopathy (CAA) lacks effective treatments. This study identifies dipeptidyl peptidase 9 (DPP9) as a potential drug target for CAA, with sitagliptin showing promise for repurposing.
Area of Science:
- Genetics and Genomics
- Neuroscience
- Pharmacology
Background:
- Cerebral amyloid angiopathy (CAA) is a common cause of hemorrhage and cognitive decline in older adults.
- Current treatments for CAA are ineffective, highlighting the urgent need for novel therapeutic targets.
- Genetic factors play a significant role in the development and progression of CAA.
Purpose of the Study:
- To identify druggable genes causally associated with Cerebral amyloid angiopathy (CAA) risk.
- To investigate dipeptidyl peptidase 9 (DPP9) as a potential therapeutic target for CAA.
- To screen for existing drugs that could be repurposed for CAA treatment.
Main Methods:
- Utilized cis-expression quantitative trait locus (cis-eQTL) data from eQTLGen and genome-wide association study (GWAS) data from FinnGen.
- Employed colocalization analysis, heterogeneity in dependent instruments (HEIDI) tests, and summary-data-based Mendelian randomization (SMR) for validation.
- Screened potential drugs using the Drug Signatures Database (DSigDB) and assessed molecular interactions via docking.
Main Results:
- Identified 10 druggable genes significantly associated with CAA risk.
- Provided strong genetic evidence for a causal link between dipeptidyl peptidase 9 (DPP9) expression and CAA.
- Sitagliptin demonstrated high binding affinity to DPP9, suggesting its potential for therapeutic repurposing in CAA.
Conclusions:
- DPP9 is a genetically validated potential drug target for Cerebral amyloid angiopathy (CAA).
- The antidiabetic drug sitagliptin shows promise for repurposing as a CAA therapeutic.
- This research offers a novel genetic approach to discovering drug targets for CAA.
Abstract:
Cerebral amyloid angiopathy (CAA), which is prevalent among older adults, constitutes a major cause of brain hemorrhage, dementia, and cognitive decline. Currently, no effective treatments for alleviating the disease of CAA exist. Hence, the discovery of novel drug targets for CAA is of utmost significance. Cis-expression quantitative trait locus (cis-eQTL) of druggable genes from eQTLGen Consortium and genome-wide association study of CAA from FinnGen database were used to screen for drug-usable genes causally associated with CAA. Robustness was assessed using colocalization analysis and heterogeneity in dependent instruments (HEIDI) tests. Significant findings were further validated using summary-data-based Mendelian randomization (SMR) with blood and arterial tissue eQTL data from eQTLGen and GTEx. Potential drugs targeting prioritized genes were screened using the DSigDB database, and binding interactions were evaluated via molecular docking. Mendelian randomization analysis identified 10 druggable genes significantly associated with CAA risk (false discovery rate < 0.1). Colocalization analysis revealed strong evidence (PPH4 > 0.75) that dipeptidyl peptidase 9 (DPP9) and CAA share a causal genetic variant. DPP9 is a member of the dipeptidyl peptidase IV family and participates in cellular energy metabolism. SMR with HEIDI test confirmed the causal relationship between genetically predicted DPP9 expression and increased CAA risk in both blood (P_SMR < 0.05, P_HEIDI>0.05) and arterial tissues (P_SMR < 0.05, P_HEIDI>0.05). Drug screening identified sitagliptin and zoledronic acid as potential DPP9-targeting compounds. Molecular docking demonstrated a highly favorable binding interaction between sitagliptin and DPP9 (binding energy = -9.0 kcal/mol). This study provides genetic evidence identifying DPP9 as a potential drug target for CAA. The antidiabetic drug sitagliptin, predicted to bind DPP9 with high affinity, represents a promising candidate for therapeutic repurposing in CAA.
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